CN110563654B - AHL structural analogue based on histidine and preparation method thereof - Google Patents
AHL structural analogue based on histidine and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an AHL structural analogue based on histidine and a preparation method thereof, belonging to the field of biological medicine. The main technical scheme is as follows: a chemical structure of a histidine-based AHL structural analogue is as follows:
wherein: n is any integer between 1 and 13. The analogue based on the histidine AHL structure provided by the invention has the advantages of simple and convenient preparation method, mild reaction conditions, simple purification method, high yield and the like. The structural analogue has obvious bacteriostatic ability on serratia marcescens.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an AHL structural analogue based on histidine and a preparation method thereof.
Background
Quorum Sensing (QS) of bacteria is a particular method of information transfer between bacterial cells. The bacteria can sense the number change of the bacteria and other bacteria in the surrounding environment by utilizing the diffusion of signal molecules among cells, and when the concentration of the signal molecules reaches a certain threshold value, the expression of related genes in the thallus can be started, and related biological functions such as the generation of virulence factors, the synthesis of extracellular polysaccharide, the formation of biofilm and the like can be regulated and controlled. Bacterial resistance has become an increasingly serious global public health problem. The improper use and abuse of broad spectrum antibiotics has led to the overwhelming prevalence of pathogenic bacterial resistance, the result of which has been a dramatic decrease in the efficacy of current antibacterial drugs. Therefore, the search for new antibacterial drugs and the establishment of new antibacterial treatment modalities have become urgent issues in the biomedical field.
Research shows that the bacterial QS system can effectively weaken the biological pathogenicity of pathogenic bacteria, and the bacteria are not directly killed in the process, so that the survival pressure of the bacteria is not generated, and the drug resistance of the bacteria to the bacteria is avoided. Quorum Sensing Inhibitors (QSIs) are expected to be powerful weapons for controlling bacterial infections and the development of drug resistance.
AHLs general structural formula
The Acyl-homoserine lactone (AHLs) -mediated gram-negative bacterial QS system is one of the major types of bacterial QS systems, first found in the marine luminescent bacterium vibrio fischeri. In natural environment, because LuxR protein in different bacteria has a special AHL acyl binding frame, each bacteria can recognize, monitor and respond to its own signal molecule. The LuxR/I QS system is widespread among gram-negative bacteria, including many important human pathogens. For example, the LasR/I system and the RhlR/I system in P.aeruginosa, the YtbR/I system in Yersinia pseudotuberculosis, the Cvir/I system in P.violaceum, etc. all have similar action modes with Vibrio fischeri. Therefore, the discovery of novel QSIs for combating gram-negative bacterial infections and solving the problem of bacterial resistance is of great practical significance.
Schiff base compounds are compounds with imino (> C = N-), and are compounds formed by condensation reaction of compounds containing active carbonyl and amine, alcohol amine and the like. Schiff base compounds have attracted much attention since their first synthesis in 1864, primarily because the imino groups in the Schiff base compounds impart some special properties to the Schiff base. Currently, schiff bases and complexes thereof are mainly applied to the aspect of medicines and are used as antibacterial agents, inhibitors, antitumor agents and the like. The Schiff base has mild reaction conditions, simple preparation method and higher synthesis efficiency, and is suitable for large-scale synthesis, and then the corresponding inhibitor is screened from the Schiff base.
Disclosure of Invention
The invention takes histidine as a structural basis, and the histidine is condensed with a series of fatty aldehydes with different carbon chain lengths to generate the AHL structural analogue with imino groups, and the compound has excellent inhibition capability on gram-negative bacteria. The invention provides theoretical support for developing inhibitors of gram-negative bacteria quorum sensing systems.
The technical scheme of the invention is as follows: a structural analogue of AHL based on histidine, the chemical formula is as follows:
wherein n is any integer between 1 and 13.
The invention also claims a preparation method of the AHL structural analogue based on histidine, under the condition of nitrogen protection, histidine and fatty aldehyde with different chain lengths react for 3-8 hours at 50-90 ℃ in a solvent mixed with alkaline substances to generate the AHL structural analogue based on histidine, and the reaction process is as follows:
wherein: 1 is an alkaline substance, and 2 is a solvent.
Further, the alkaline substance is an inorganic base.
Further, the inorganic base is potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate, and the solvent is methanol, ethanol, dichloromethane or diethyl ether.
The invention has the following beneficial effects:
(1) The preparation method based on the histidine AHL structural analogue provided by the invention is simple and easy to implement, and has the advantages of mild reaction conditions, simple purification method, high yield and the like.
(2) The histidine-based AHL structural analogue designed by the invention has a structure very similar to that of gram-negative bacteria quorum sensing signal molecules AHLs, has a five-membered aromatic ring and is connected with a long-chain aliphatic tail. It has obvious bacteriostasis capacity to serratia marcescens.
Drawings
FIG. 1 shows n-heptaldehyde histidine Schiff base 1 H nuclear magnetic spectrum;
FIG. 2 shows n-octanal histidine Schiff base 1 H nuclear magnetic spectrum;
FIG. 3 shows decanal histidine Schiff base 1 H nuclear magnetic spectrum;
FIG. 4 shows dodecanal histidine Schiff base 1 H nuclear magnetic spectrum;
FIG. 5 is a graph showing the time-dependent change of bacteriostatic effect of 5. Mu. Mol/mL histidine Schiff base;
FIG. 6 is a graph showing the bacteriostatic effect of 2.5. Mu. Mol/mL histidine Schiff base as a function of time;
FIG. 7 is a graph showing the time-dependent bacteriostatic effect of 1. Mu. Mol/mL histidine Schiff base;
FIG. 8 is a graph showing the time-dependent effect of histidine Schiff base inhibition at 0.5. Mu. Mol/mL.
Detailed Description
The present invention will be further described with reference to specific examples, but the starting materials for the present invention are commercially available unless otherwise specified.
EXAMPLE 1 preparation of histidine-n-heptanal Schiff base (G-Z)
10mmol of histidine and 10mmol of potassium hydroxide are added into a round-bottom flask containing 60mL of absolute ethanol, and the mixture is stirred and dissolved at 50 ℃ under the protection of nitrogen. 20mmol of n-heptanal was dissolved in 20mL of anhydrous methanol, slowly added dropwise to a round-bottom flask and stirred at 55 ℃ for 3h. After the reaction, the reaction mixture was cooled to room temperature, and unreacted histidine was removed by suction filtration. The filtrate solution was evaporated under reduced pressure (40 ℃ C.) to give a pale yellow solid. The product was placed in a 20mL centrifuge tube, 15mL acetone was added, washed with ultrasound for 10 minutes, centrifuged at 7000rpm/min for 3 minutes, washed 10 times in total to give a pale yellow solid, which was dried in vacuo to give a pale yellow solid in 74.6% yield.
Nuclear magnetic data of histidine-n-heptanal schiff base are shown in figure 1: 1 H NMR(400MHz，D 2 O)，δ7.72(d,J＝9.6Hz,1H)，7.63(d,J＝4.1Hz,1H)，6.97(s，1H)，3.60(dd,J＝7.7,5.2Hz,1H),3.51(dd,J＝11.3,4.4Hz,2H)3.09–2.95(m,2H),2.96–2.85(m,2H),1.53–1.14(m,6H),0.90(q,J＝7.8,6.9Hz,3H)ppm。
EXAMPLE 2 preparation of histidine-n-octanal Schiff base (X-Z)
10mmol of histidine and 10mmol of sodium hydroxide are added into a round-bottomed flask containing 60mL of absolute ethanol, and the mixture is stirred and dissolved at 50 ℃ under the protection of nitrogen. 20mmol of n-octanal is dissolved in 20mL of absolute ethanol, slowly added dropwise to a round-bottom flask and stirred for 3h at 55 ℃. After the reaction, the reaction mixture was cooled to room temperature, and unreacted histidine was removed by suction filtration. The filtrate solution was evaporated under reduced pressure (40 ℃ C.) to give a pale yellow solid. The product was placed in a 20mL centrifuge tube, 15mL acetone was added, washed with ultrasound for 10 minutes, centrifuged at 7000rpm/min for 3 minutes, washed 10 times in total to give a pale yellow solid, which was dried in vacuo to give a pale yellow solid in 74.4% yield.
The nuclear magnetic data of histidine n-octanal schiff base is shown in figure 2: 1 H NMR(400MHz，D 2 O)，δ7.70(d,J＝6.8Hz,1H),7.62(d,J＝3.9Hz,1H),6.95(s,1H),3.57(s,1H),3.49(dd,J＝11.3,4.5Hz,2H),3.00(s,2H),2.93–2.85(m,2H),1.30(s,8H),0.89(s,3H)ppm。
EXAMPLE 3 preparation of Schiff base histidine decanal (U-Z)
10mmol of histidine and 10mmol of sodium carbonate are added into a round-bottom flask containing 60mL of absolute ethyl alcohol, and the mixture is stirred and dissolved at 50 ℃ under the protection of nitrogen. 20mmol decanal was dissolved in 20mL absolute ethanol, slowly added dropwise to the round bottom flask and stirred for 8h at 55 ℃. After the reaction, the reaction mixture was cooled to room temperature, and unreacted histidine was removed by suction filtration. The filtrate solution was evaporated under reduced pressure (40 ℃ C.) to give a pale yellow solid. The product was placed in a 20mL centrifuge tube, 15mL acetone was added, washed with ultrasound for 10 minutes, centrifuged at 7000rpm/min for 3 minutes, washed 10 times in total to give a pale yellow solid, which was dried in vacuo to give a pale yellow solid in 64.9% yield.
HistidineNuclear magnetic data of decanol acid schiff base are shown in fig. 3: 1 H NMR(400MHz，D 2 O)，δ7.70(s,1H),7.50(s,1H),6.95(s,1H),3.56(dd,J＝7.6,5.2Hz,2H),3.48(dd,J＝5.1Hz,1H),2.99(td,J＝16.3,15.6,6.2Hz,2H),2.86(dd,J＝14.8,7.7Hz,2H),1.45–1.13(m,12H),0.97–0.76(m,3H)ppm。
EXAMPLE 4 preparation of histidine dodecanal Schiff base (S-Z)
10mmol of histidine and 10mmol of potassium carbonate are added into a round-bottom flask containing 60mL of absolute ethyl alcohol, and the mixture is stirred and dissolved at 50 ℃ under the protection of nitrogen. 20mmol dodecanal was dissolved in 20mL of anhydrous methanol, slowly added dropwise to the round bottom flask, and stirred at 90 ℃ for 3h. After the reaction, the reaction mixture was cooled to room temperature, and unreacted histidine was removed by suction filtration. The filtrate solution was evaporated under reduced pressure (40 ℃ C.) to give a pale yellow solid. The product was placed in a 20mL centrifuge tube, 15mL acetone was added, washed with ultrasound for 10 minutes, centrifuged at 7000rpm/min for 3 minutes, washed 10 times in total to give a pale yellow solid, which was dried in vacuo to give a pale yellow solid with a yield of 65.2%.
Nuclear magnetic data of histidine dodecanal schiff base are shown in figure 4: 1 H NMR(400MHz，D 2 O)，δ7.70(s,1H),7.43(s,1H),6.96(s,1H),3.54(s,1H),3.46(s,1H),2.98(s,2H),2.87(s,2H),1.30(s,16H),0.89(s,3H)ppm。
example 5 inhibition of Serratia marcescens by histidine-based AHL structural analogues
Preparing a histidine fatty aldehyde Schiff base solution: in an ultra-clean workbench, sterile water is used as a solvent, and histidine-n-heptaldehyde Schiff base, histidine-n-octaldehyde Schiff base, histidine-decanaldehyde Schiff base and histidine-dodecanal Schiff base are respectively prepared into solutions according to the concentrations of 5 mu mol/mL, 2.5 mu mol/mL, 1 mu mol/mL and 0.5 mu mol/mL.
LB medium: 10g of tryptone, 5g of yeast powder and 10g of sodium chloride are added with deionized water to be constant volume to 1 liter, and the mixture is sterilized for 30min at 120 ℃.
In a clean bench, four histidine fatty acid schiff bases at different concentrations were added to each of the 1 st to 8 th columns (two columns per sample) of a sterilized 96-well plate at 50. Mu.L per well, followed by adding 100. Mu.L of LB liquid medium containing Serratia marcescens to each well. 150 μ L of sterile LB liquid medium was added to each well of column 9; adding 150 mu L of sterile water into each hole of the 10 th row and the 11 th row; 150. Mu.L of LB liquid medium containing Serratia marcescens was added to each well of column 12.
Placing 96-well plate into 30 deg.C shaking table, performing constant temperature shaking culture for 12 hr, and measuring OD every 2 hr 600nm The value is obtained.
As shown in the results of figures 5-8, the synthesized AHL structural analogue histidine fatty aldehyde Schiff base has obvious inhibition effect on the growth of Serratia marcescens, wherein the histidine dodecanal Schiff base has the best bacteriostasis effect.
The foregoing examples are provided for illustration and description of the invention only and are not intended to limit the invention to the scope of the described examples. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that many variations and modifications may be made in accordance with the teachings of the present invention, which variations and modifications are within the scope of the present invention as claimed.
Claims (4)
1. A histidine-based AHL structural analogue of the formula:
2. the method of claim 1, wherein histidine is reacted with fatty aldehydes of different chain lengths in a solvent mixed with an alkaline substance at 50-90 ℃ for 3-8 hours under nitrogen protection to form the structural analogue of AHL.
3. The method of making an AHL structural analog of histidine as in claim 2, wherein said basic substance is an inorganic base.
4. A method of preparing an AHL structural analog based on histidine as in claim 3, wherein said inorganic base is potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate, and said solvent is methanol, ethanol, dichloromethane or diethyl ether.
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| 2310305-94-1等;STN;《REGISTRY》;20190517 * |
| Differential-pulse polarography of amino acids in acetaldehyde-borax;PEIBIAO LI等;《Analytica Chimica Acta》;19901231;第236卷;第307-313页 * |
| Effective Cleavage of b-1,4-Glycosidic Bond by Functional Micelle with L-Histidine Residue;Xiao-Hong Liao 等;《Catal. Lett.》;20160415;第146卷;第1249-1255页 * |
| 氨基酸席夫碱的合成及性质研究;赵小菁等;《有机化学》;20111231;第31卷(第9期);第1516-1521页 * |
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